Characteristics of the low-energy reporters in a longitudinal national dietary survey.
The aim of the present study was to establish whether the characteristics of members of a large national birth cohort study who submitted diet diaries with implausibly low-energy intake differed from those whose recorded energy intake was more plausible. Survey members (n 1898) recorded their diets in a 7 d diary in household measures. Those whose reported energy intake (EI) as a fraction of their estimated BMR was less than 1.10, here termed low-energy reporters (LER) but often called under-reporters, constituted 20.6% of the study population. None of the variables describing dietary, smoking or exercise behaviour bore a significant relationship with low EI/BMR (< 1.10), neither did those describing region of residence, subjective adequacy of income, current social class, social relations or the social environment of the subjects. Results of logistic regression analysis showed that the only independently significant characteristic for men was higher BMI. In women, in addition to higher BMI, having been overweight or obese as an adult independently, but less significantly, predicted low EI/BMR, while membership as a child of social class III (non-manual), having more children in the household and having a paid job marginally but independently decreased the probability of reporting low EI/BMR. Submission of a diary with EI/BMR < 1.10 7 years earlier in the same survey was an even more powerful predictor of current low EI/BMR than higher BMI in both sexes. The average reported diet-composition of LER was more micronutrient- and protein-rich than that of the others, indicating different dietary, or diet-recording, behaviour in this group of subjects. LER are not a random sample of the survey population, and their characteristics, definable to some extent, put them at risk for lower health status. Although EI/BMR cut-off points can be used to identify LER, the problem of how to use their data is still unresolved.


Identification of factors influencing shark catch and mortality in the Marshall Islands tuna longline fishery and management implications.
Recent average annual catches of sharks by tuna longline vessels fishing in the Republic of the Marshall Islands (RMI) are estimated to be between 1583 and 2274 t. Although 22 shark species have been recorded by the observer programme for this fishery, 80% of the annual catch comprises only five species: blue shark Prionace glauca, silky shark Carcharhinus falciformis, bigeye thresher shark Alopias superciliosus, pelagic thresher shark Alopias pelagicus and oceanic whitetip shark Carcharhinus longimanus. Wire leaders (i.e. branch lines or traces) were also used by nearly all observed vessels. Generalized additive model (GAM)-based analyses of catch rates indicated that P. glauca and A. superciliosus are caught in higher numbers when vessels fish in relatively cooler waters, at night, close to the full moon, when the 27° C thermocline is close to the surface and during El Niño conditions. In contrast, C. falciformis, A. pelagicus and C. longimanus are caught in higher numbers when shark lines are used (all three species) or hooks are set at a shallow depth (A. pelagicus and C. longimanus and, also, P. glauca). These findings are generally consistent with current knowledge of these species' habitat preferences, movement and distribution. The results of these analyses were combined with information pertaining to shark condition and fate upon capture to compare the likely effectiveness of a range of potential measures for reducing shark mortality in the longline fishery. Of the options considered, the most effective would be to combine measures that reduce the catch rate (e.g. restrictions on the use of wire leaders, shark baits and shark lines) with measures that increase survival rates after post-capture release (e.g. finning bans).


Selective microtubule-based transport of dendritic membrane proteins arises in concert with axon specification.
The polarized distribution of membrane proteins to axonal or somatodendritic neuronal compartments is fundamental to nearly every aspect of neuronal function. The polarity of dendritic proteins depends on selective microtubule-based transport; the vesicles that carry these proteins are transported into dendrites but do not enter the axon. We used live-cell imaging of fluorescently tagged dendritic and axonal proteins combined with immunostaining for initial segment and cytoskeletal markers to evaluate different models of dendrite-selective transport in cultured rat hippocampal neurons. In mature neurons, dendritic vesicles that entered the base of the axon stopped at the proximal edge of the axon initial segment, defined by immunostaining for ankyrinG, rather than moving into the initial segment itself. In contrast, axonal vesicles passed through the initial segment without impediment. During development, dendrite-selective transport was detected shortly after axons formed, several days before initial segment assembly, before the appearance of a dense actin meshwork in the initial segment, and before dendrites acquire microtubules of mixed polarity orientation. Indeed, some elements of selective transport were detected even before axon specification. These findings are inconsistent with models for selective transport that depend on the presence of an F-actin-based cytoplasmic filter in the initial segment or that posit that transport into dendrites is mediated by dyneins translocating along minus-end out microtubules. Instead our results suggest that selective transport involves the coordinated regulation of the different motor proteins that mediate dendritic vesicle transport and that the selectivity of motor-microtubule interactions is one facet of this process.


Reflex muscle contraction in anterior shoulder instability.
Reduced proprioception may contribute to recurrent anterior shoulder instability. Twelve patients with unilateral shoulder instability were investigated for evidence of deficient proprioception with an activated pneumatic cylinder and surface electromyography electrodes; the contralateral normal shoulder was used as a control. The latency between onset of movement and the detection of muscle contraction was used as an index of proprioception. No significant difference in muscle contraction latency was detected between the stable and unstable shoulders, suggesting that there was no significant defect in muscular reflex activity. This study does not support the use proprioception-enhancing physiotherapy in the treatment of posttraumatic anterior shoulder instability.


Development and Application of the Remote Food Photography Method to Measure Food Intake in Exclusively Milk Fed Infants: A Laboratory-Based Study.
Accurate methods of assessing food intake in infants are needed to assess the relationship between infant feeding practices and risk of childhood obesity. Current methods are either subjective or have limited ability for use beyond clinical research settings. To assess the accuracy of the RFPM to evaluate simulated milk intake including energy, macronutrient, and micronutrient intake compared to direct weighing within a controlled study. Individuals were recruited to prepare three 2 fl oz, 4 fl oz, 6 fl oz, and 8 fl oz servings of infant formula and to capture photographs at different stages of preparation (dry powdered formula, prepared formula, and liquid waste) using the SmartIntake® application. Gram weights of the bottles were obtained by the RFPM and direct weighing. Using the United States Department of Agriculture National Nutrient Database for Standard Reference, energy, macronutrient, and micronutrient values were generated from gram weights. Intake of formula prepared from powder measured by the RFPM was equivalent to weighed intake within 7.5% equivalence bounds among all servings and each serving size. The mean difference between methods varied among servings sizes with the RFPM underestimating intake by 1.6 ± 0.4 kcals in 2 fl oz servings, 4.8 ± 0.6 kcals in 4 fl oz servings, and 6.2 ± 1.0 kcals in 6 fl oz servings, and overestimating intake by 0.1 ± 1.2 kcals in 8 fl oz servings. Bland-Altman analysis showed that the RFPM overestimated intake at lower levels food intake and underestimated intake at higher levels. Considering photographs of only the prepared formula bottle and the bottle with formula waste to simulate ready-to-feed formula and human breast milk, intake estimated by the RFPM was equivalent to the directly weighed intake within 7.5% for all servings. The RFPM has higher accuracy than subjective methods and similar accuracy as compared to the objective methods in estimating simulated intake of milk and formula with lower burden to caregivers. The RFPM is a viable method for measuring intake in exclusively milk fed infants by caregivers in a controlled environment with potential for widespread use in research and clinical practice.


Clonal species Trichoderma parareesei sp. nov. likely resembles the ancestor of the cellulase producer Hypocrea jecorina/T. reesei.
We have previously reported that the prominent industrial enzyme producer Trichoderma reesei (teleomorph Hypocrea jecorina; Hypocreales, Ascomycota, Dikarya) has a genetically isolated, sympatric sister species devoid of sexual reproduction and which is constituted by the majority of anamorphic strains previously attributed to H. jecorina/T. reesei. In this paper we present the formal taxonomic description of this new species, T. parareesei, complemented by multivariate phenotype profiling and molecular evolutionary examination. A phylogenetic analysis of relatively conserved loci, such as coding fragments of the RNA polymerase B subunit II (rpb2) and GH18 chitinase (chi18-5), showed that T. parareesei is genetically invariable and likely resembles the ancestor which gave raise to H. jecorina. This and the fact that at least one mating type gene of T. parareesei has previously been found to be essentially altered compared to the sequence of H. jecorina/T. reesei indicate that divergence probably occurred due to the impaired functionality of the mating system in the hypothetical ancestor of both species. In contrast, we show that the sexually reproducing and correspondingly more polymorphic H. jecorina/T. reesei is essentially evolutionarily derived. Phenotype microarray analyses performed at seven temperature regimens support our previous speculations that T. parareesei possesses a relatively high opportunistic potential, which probably ensured the survival of this species in ancient and sustainable environment such as tropical forests.


Hydrodynamic pressure sensing with an artificial lateral line in steady and unsteady flows.
With the overall goal being a better understanding of the sensing environment from the local perspective of a situated agent, we studied uniform flows and Kármán vortex streets in a frame of reference relevant to a fish or swimming robot. We visualized each flow regime with digital particle image velocimetry and then took local measurements using a rigid body with laterally distributed parallel pressure sensor arrays. Time and frequency domain methods were used to characterize hydrodynamically relevant scenarios in steady and unsteady flows for control applications. Here we report that a distributed pressure sensing mechanism has the capability to discriminate Kármán vortex streets from uniform flows, and determine the orientation and position of the platform with respect to the incoming flow and the centre axis of the Kármán vortex street. It also enables the computation of hydrodynamic features which may be relevant for a robot while interacting with the flow, such as vortex shedding frequency, vortex travelling speed and downstream distance between vortices. A Kármán vortex street was distinguished in this study from uniform flows by analysing the magnitude of fluctuations present in the sensor measurements and the number of sensors detecting the same dominant frequency. In the Kármán vortex street the turbulence intensity was 30% higher than that in the uniform flow and the sensors collectively sensed the vortex shedding frequency as the dominant frequency. The position and orientation of the sensor platform were determined via a comparative analysis between laterally distributed sensor arrays; the vortex travelling speed was estimated via a cross-correlation analysis among the sensors.


Toward a more professional and practical medical education: a novel Central European approach.
We here present an innovative curriculum for a complete medical education that conforms to the current European Bologna system of academic training. The curriculum aims at raising doctors who are excellently prepared for clinical work over as short a time as 5 years; it provides a comprehensive, yet shorter than usual, education that strongly pronounces the importance of increasing the students' practical clinical competences and rigorously excludes superfluous contents. The curriculum encompasses 52 modules, 32 at the bachelor's and 20 at the master's level. Already at the level of the bachelor degree, full employability is given; the students finish the master's course as medical doctors optimally prepared to manage patients at the level of postgraduate medical education. The structure of the curriculum is modular; each modular component is essential for medical education and contains an average of five European Credit Transfer System credits, amounting to 150 hours of education. Depending on the subspecialty, the courses include lectures, seminars, practical laboratory training, and clinical training at varying quantities. In addition to attendance times, sufficient time slots are prepared for self-study in lectures, seminars, and practical work. With our curriculum, we provide an easily applicable backbone for a modern course of medicine that can be installed also at smaller academic institutions.


2017 Taiwan lipid guidelines for high risk patients.
In Taiwan, the prevalence of hyperlipidemia increased due to lifestyle and dietary habit changes. Low density lipoprotein cholesterol (LDL-C) and non-high density lipoprotein cholesterol (non-HDL-C) are all significant predicting factors of coronary artery disease in Taiwan. We recognized that lipid control is especially important in patients with existed atherosclerotic cardiovascular diseases (ASCVD), including coronary artery disease (CAD), ischemic stroke and peripheral arterial disease (PAD). Because the risk of ASCVD is high in patients with diabetes mellitus (DM), chronic kidney disease (CKD) and familial hypercholesterolemia (FH), lipid control is also necessary in these patients. Lifestyle modification is the first step to control lipid. Weight reduction, regular physical exercise and limitation of alcohol intake all reduce triglyceride (TG) levels. Lipid-lowering drugs include HMG-CoA reductase inhibitors (statins), cholesterol absorption inhibitors (ezetimibe), proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, nicotinic acids (niacin), fibric acids derivatives (fibrates), and long-chain omega-3 fatty acids. Statin is usually the first line therapy. Combination therapy with statin and other lipid-lowering agents may be considered in some clinical settings. For patients with acute coronary syndrome (ACS) and stable CAD, LDL-C < 70 mg/dL is the major target. A lower target of LDL-C <55 mg/dL can be considered in ACS patients with DM. After treating LDL-C to target, non-HDL-C can be considered as a secondary target for patients with TG ≥ 200 mg/dL. The suggested non-HDL-C target is < 100 mg/dL in ACS and CAD patients. For patients with ischemic stroke or transient ischemic attack presumed to be of atherosclerotic origin, statin therapy is beneficial and LDL-C < 100 mg/dL is the suggested target. For patients with symptomatic carotid stenosis or intracranial arterial stenosis, in addition to antiplatelets and blood pressure control, LDL-C should be lowered to < 100 mg/dL. Statin is necessary for DM patients with CV disease and the LDL-C target is < 70 mg/dL. For diabetic patients who are ≥ 40 years of age, or who are < 40 years of age but have additional CV risk factors, the LDL-C target should be < 100 mg/dL. After achieving LDL-C target, combination of other lipid-lowering agents with statin is reasonable to attain TG < 150 mg/dL and HDL-C >40 in men and >50 mg/dL in women in DM. LDL-C increased CV risk in patients with CKD. In adults with glomerular filtration rate (GFR) < 60 mL/min/1.73m2 without chronic dialysis (CKD stage 3-5), statin therapy should be initiated if LDL-C ≥ 100 mg/dL. Ezetimibe can be added to statin to consolidate the CV protection in CKD patients. Mutations in LDL receptor, apolipoprotein B and PCSK9 genes are the common causes of FH. Diagnosis of FH usually depends on family history, clinical history of premature CAD, physical findings of xanthoma or corneal arcus and high levels of LDL-C. In addition to conventional lipid lowering therapies, adjunctive treatment with mipomersen, lomitapide, or PCSK9 inhibitors become necessary to further reduce LDL-C in patients with FH. Overall, these recommendations are to help the health care professionals in Taiwan to treat hyperlipidemia with current scientific evidences. We hope the prescription rate of lipid lowering drugs and control rate of hyperlipidemia in high risk patients could be increased by implementation of the clinical guidelines. The major purpose is to improve clinical outcomes of these high risk patients through the control of hyperlipidemia.


An automated and reliable method for breath detection during variable mask pressures in awake and sleeping humans.
Accurate breath detection is crucial in sleep and respiratory physiology research and in several clinical settings. However, this process is technically challenging due to measurement and physiological artifacts and other factors such as variable leaks in the breathing circuit. Recently developed techniques to quantify the multiple causes of obstructive sleep apnea, require intermittent changes in airway pressure applied to a breathing mask. This presents an additional unique challenge for breath detection. Traditional algorithms often require drift correction. However, this is an empirical operation potentially prone to human error. This paper presents a new algorithm for breath detection during variable mask pressures in awake and sleeping humans based on physiological landmarks detected in the airflow or epiglottic pressure signal (Pepi). The algorithms were validated using simulated data from a mathematical model and against the standard visual detection approach in 4 healthy individuals and 6 patients with sleep apnea during variable mask pressure conditions. Using the flow signal, the algorithm correctly identified 97.6% of breaths with a mean difference±SD in the onsets of respiratory phase compared to expert visual detection of 23±89ms for inspiration and 6±56ms for expiration during wakefulness and 10±74ms for inspiration and 3±28 ms for expiration with variable mask pressures during sleep. Using the Pepi signal, the algorithm correctly identified 89% of the breaths with accuracy of 31±156ms for inspiration and 9±147ms for expiration compared to expert visual detection during variable mask pressures asleep. The algorithm had excellent performance in response to baseline drifts and noise during variable mask pressure conditions. This new algorithm can be used for accurate breath detection including during variable mask pressure conditions which represents a major advance over existing time-consuming manual approaches.


Rhythm reproduction in kindergarten, reading performance at second grade, and developmental dyslexia theories.
Temporal processing deficit could be associated with a specific difficulty in learning to read. In 1951, Stambak provided preliminary evidence that children with dyslexia performed less well than good readers in reproduction of 21 rhythmic patterns. Stambak's task was administered to 1,028 French children aged 5-6 years. The score distribution (from 0 to 21) was quasi-normal, with some children failing completely and other performing perfectly. In second grade, reading was assessed in 695 of these children. Kindergarten variables explained 26% of the variance of the reading score at second grade. The Stambak score was strongly and linearly related to reading performance in second grade, after partialling out performance on other tasks (oral repetition, attention, and visuo-spatial tasks) and socio-cultural level. Findings are discussed in relation to perceptual, cerebellar, intermodal, and attention-related theories of developmental dyslexia. It is concluded that simple rhythm reproduction tasks in kindergarten are predictive of later reading performance.


Differential effect of CDP-choline on brain cytosolic choline levels in younger and older subjects as measured by proton magnetic resonance spectroscopy.
Phosphatidylcholine (PtdCho), which is essential for membrane integrity and repair, is reduced in brain cell membranes with age. Evidence from both animal and in vitro studies indicates that cytidine 5' diphosphate choline (CDP-choline) can increase the synthesis of PtdCho; however, the effect of CDP-choline on brain choline metabolism has not previously been studied in human subjects. In this study, in vivo proton magnetic resonance spectroscopy (1H-MRS) was used to measure brain levels of cytosolic, choline-containing compounds before and after single oral doses of CDP-choline. Three hours after dosing, plasma choline increased similarly in younger (mean age 25 years) and older subjects (mean age 59 years). However, while the choline resonance in brain increased by 18% on average in younger subjects, it decreased by almost 6% in older subjects (P = 0.028). These results may be explained by a previously observed decrease in brain choline uptake, but not cytidine uptake, in older subjects. Additional intracellular cytidine following the administration of CDP-choline should lead to the increased incorporation of choline already present in brain into membrane PtdCho, which is not MRS-visible, consequently lowering the brain choline resonance below that of pre-treatment values. These results suggest that the cytidine moiety of CDP-choline stimulates phosphatidylcholine synthesis in human brain cell membranes in older subjects.


Oxygen-atom vacancy formation and reactivity in polyoxovanadate clusters.
Reducible metal oxides (RMOs) are widely used materials in heterogeneous catalysis due to their ability to facilitate the conversion of energy-poor substrates to energy-rich chemical fuels and feedstocks. Theoretical investigations have modeled the role of RMOs in catalysis and found they traditionally follow a mechanism in which the generation of oxygen-atom vacancies is crucial for the high activity of these solid supports. However, limited spectroscopic techniques for in situ analysis renders the identification of the reactivity of individual oxygen-atom vacancies on RMOs challenging. These obstacles can be circumvented through the use of homogeneous complexes as molecular models for metal oxides, such as polyoxometalates. Summarized herein, a sub-class of polyoxometalates, polyoxovanadate-alkoxide clusters, ([V6O7(OR)12]n; R = CH3, C2H5; n = 2-, 1-, 0), are explored as homogeneous molecular models for bulk vanadium oxide. A series of synthetic strategies have been employed to access oxygen-deficient vanadium oxide assemblies, including addition of V(Mes)3(thf), tertiary phosphanes, and organic acids to plenary Lindqvist motifs. We further detail investigations surrounding the ability of these oxygen-deficient sites to mediate reductive transformations such as O2 and NOx1- (x = 2, 3) activation.


Sagittal and coronal dimensions of the ethmoid roof: a radioanatomic study.
Understanding the anatomy of the ethmoid roof is critical to safe surgical outcomes. Normative data regarding the height and slope of this region have been somewhat limited, derived primarily from cadaveric coronal computed tomography (CT) studies. With triplanar imaging programs, precise multidimensional measurements of the ethmoid roof are now possible. We present a radioanatomic study to characterize normative sagittal and coronal dimensions of the ethmoid roof. Bilateral measurements were taken in 100 consecutive sinus CT scans using ThinClient 3D software. In the sagittal plane, the height of the ethmoid roof was measured in quadrants at five equidistant points between the frontal beak and sphenoid face, referencing the nasal floor. In the coronal plane, the ethmoid roof was measured at three points at the level of the anterior ethmoid artery and at two points at the junction of the posterior ethmoid and sphenoid sinuses. When examined sagittally, the right side showed significantly lower skull base heights in the anterior ethmoid compared with the left side (59.0 mm versus 59.8 mm, p = 0.017; 53.7 mm versus 54.5 mm, p = 0.0004). Coronal measurements of the anterior ethmoid roof showed similar significant differences. The anterior ethmoid roof had greater asymmetries of height compared with the posterior ethmoid roof, which was fairly constant. This study provides numerical correlates to accepted concepts regarding the shape and slope of the ethmoid roof. Differences in height of the skull base between right and left sides, especially in the anterior ethmoid sinus, may be an important surgical consideration. The posterior ethmoid roof appears to be relatively constant and should serve as a reliable surgical landmark.


Bridging the Gap Between Computational Photography and Visual Recognition.
What is the current state-of-the-art for image restoration and enhancement applied to degraded images acquired under less than ideal circumstances? Can the application of such algorithms as a pre-processing step improve image interpretability for manual analysis or automatic visual recognition to classify scene content? While there have been important advances in the area of computational photography to restore or enhance the visual quality of an image, the capabilities of such techniques have not always translated in a useful way to visual recognition tasks. Consequently, there is a pressing need for the development of algorithms that are designed for the joint problem of improving visual appearance and recognition, which will be an enabling factor for the deployment of visual recognition tools in many real-world scenarios. To address this, we introduce the UG 2 dataset as a large-scale benchmark composed of video imagery captured under challenging conditions, and two enhancement tasks designed to test algorithmic impact on visual quality and automatic object recognition. Furthermore, we propose a set of metrics to evaluate the joint improvement of such tasks as well as individual algorithmic advances, including a novel psychophysics-based evaluation regime for human assessment and a realistic set of quantitative measures for object recognition performance. We introduce six new algorithms for image restoration or enhancement, which were created as part of the IARPA sponsored UG 2 Challenge workshop held at CVPR 2018. Under the proposed evaluation regime, we present an in-depth analysis of these algorithms and a host of deep learning-based and classic baseline approaches. From the observed results, it is evident that we are in the early days of building a bridge between computational photography and visual recognition, leaving many opportunities for innovation in this area.


The effect of cingulate cortex lesions on task switching and working memory.
Anatomic interconnections between the prefrontal and anterior cingulate cortices suggest that these areas may have similar functions. Here we report the effect of anterior cingulate removal on task switching, error monitoring, and working memory. Neuroimaging studies have implicated the cingulate cortex in all these processes. Six macaques were taught task switching (TS) and delayed alternation (DA) paradigms. TS required switching between two conditional response tasks with mutually incompatible response selection rules. DA required alternation between two identically covered food-well positions. In the first set of experiments, anterior cingulate lesions did not consistently impair TS or DA performance. One animal performed worst on both TS and DA and in this animal the cingulate sulcus lesion was most complete. In the second set of experiments, we confirmed that larger anterior cingulate lesions, which included the sulcus, consistently impaired TS but only led to a mild and equivocal impairment of DA. The TS error pattern, however, did not suggest an impairment of TS per se. The consequence of a cingulate lesion is, therefore, distinct to that of a prefrontal lesion. TS error distribution analyses provided some support for a cingulate role in monitoring responses for errors and subsequent correction but the pattern of reaction time change in TS was also indicative of a failure to sustain attention to the task and the responses being made.


Improvements in the accuracy and the repeatability of long trace profiler measurements.
Modifications of the long trace profiler at the Advanced Photon Source at Argonne National Laboratory have significantly improved its accuracy and repeatability for measuring the figure of large flat and long-radius mirrors. Use of a Dove prism in the reference beam path corrects phasing problems between mechanical errors and thermally induced system errors. A single reference correction now completely removes both of these error signals from the measured surface profile. The addition of a precision air conditioner keeps the temperature in the metrology enclosure constant to within +/-0.1 degrees C over a 24-h period and has significantly improved the stability and the repeatability of the measurements. Long-radius surface curvatures can now be measured absolutely with a high degree of confidence. These improved capabilities are illustrated with a series of measurements of a 500-mm-long mirror with a 5-km radius of curvature. The standard deviation in the average of ten slope profile scans is 0.3 microrad, and the corresponding standard deviation in the height error is 4.6 nm.


The capacity to consent to treatment in amyotrophic lateral sclerosis: a preliminary report.
Facing the relentless worsening of their condition, ALS patients are required to make decisions on treatments and end-of-life care. A cognitive impairment showed to be a negative prognostic factor in ALS patients, perhaps affecting the ability to make informed decisions. Notwithstanding its crucial role, the capacity to consent to treatment (CCT) has never been evaluated in these patients. To assess the CCT in an ALS cohort in comparison to a control group, and to study the effects of demographic and clinical variables on this high-level cognitive function. 102 ALS patients and 106 healthy controls (HC) were enrolled. CCT was assessed using the MacArthur Competence Assessment Tool for Treatment (MAC-CAT-T) and the performance was classified into the three CCT outcomes (full credit, partial credit, no credit). Cognitive and psychological variables were assessed by MMSE, phonemic fluencies, Frontal System Behavioural Scale (FrSBe), and ALS Depression Inventory (ADI). Clinical and demographic variables were analyzed as possible predictors of the MAC-CAT-T outcomes. After a 1-year follow-up, CCT and neuropsychological assessments were repeated. Most ALS patients (i.e., from 75 to 83% according to the different sub-items) retain full CCT. However, a subpopulation of the ALS patients showed a reduced CCT with respect to the HC. Age, education, phonemic fluency, and depression appeared related to the CCT outcomes. After 1 year, only the reasoning items worsened. This is a preliminary report suggesting that the large majority of ALS patients can retain full ability to choose between treatment options. However, demographic and neuropsychological variables may affect CCT, pointing to the need for special attention to the consent disclosure in this disease.


Estimation of recombination frequencies and construction of RFLP linkage maps in plants from crosses between heterozygous parents.
The construction of a restriction fragment length polymorphism (RFLP) linkage map is based on the estimation of recombination frequencies between genetic loci and on the determination of the linear order of loci in linkage groups. RFLP loci can be identified as segregations of singular or allelic DNA-restriction fragments. From crosses between heterozygous individuals several allele (fragment) configurations are possible, and this leads to a set of formulas for the evaluation of p, the recombination frequency between two loci. Tables and figures are presented illustrating a general outline of gene mapping using heterozygous populations. The method encompasses as special cases the mapping of loci from segregating populations of pure lines. Formulas for deriving the recombination frequencies and information functions are given for different fragment configurations. Information functions derived for relevant configurations are also compared. A procedure for map construction is presented, as it has been applied to RFLP mapping in an allogamous crop.


Correlates of frequent alcohol consumption among middle-aged and older men and women in Russia: A multilevel analysis of the PrivMort retrospective cohort study.
A large proportion of premature deaths in Russia since the early 1990s, following the transition from communism, have been attributed to hazardous drinking. Little is known about the correlates of alcohol consumption. We present new data on the consumption of alcoholic beverages among middle-aged and older Russians and identify socio-demographic, socio-economic, and life-course correlates of frequent drinking. Within the framework of the PrivMort project, conducted in 30 industrial towns in the European part of Russia, we acquired information on the frequency of drinking among 22,796 respondents and 57,907 of their surviving and deceased relatives. We fit three-level mixed-effects logistic regression models of frequent drinking in which respondents' relatives, aged 40 and over, are nested in their families and towns. Deceased male relatives consumed alcohol significantly more often, while deceased female relatives consumed alcohol significantly less often than the respondents of corresponding gender. In a multivariable analysis, we found that individuals' education, communication with family members, labour market status, history of unemployment, and occupational attainment are all significant correlates of frequent drinking in Russia. These associations are stronger among men rather than among women. There are significant differences between frequency of drinking among surviving and deceased individuals and frequent drinking is associated with a wide array of individual socio-demographic, socio-economic, and life course factors that can partially explain high alcohol consumption in post-communist Russia.


Reversible biomechano-responsive surface based on green fluorescent protein genetically modified with unnatural amino acids.
GFP has been genetically modified at two specific positions of its molecular architecture. These modifications allow its covalent attachment onto PEG brushes grafted on functionalized silicone surfaces. The stretching of this material leads to a reversible decrease of the fluorescence intensity due to stretch-induced forces applying on GFP molecules.


The cysteine-rich core domain of REIC/Dkk-3 is critical for its effect on monocyte differentiation and tumor regression.
Reduced expression in immortalized cells (REIC)/Dickkopf (Dkk)-3 is a tumor-suppressor gene and has been studied as a promising therapeutic gene for cancer gene therapy. Intratumoral injection of an adenovirus vector carrying the human REIC/Dkk-3 gene (Ad-REIC) elicits cancer cell-specific apoptosis and anticancer immune responses. The cytokine-like effect of secretory REIC/Dkk-3 on the induction of dendritic cell (DC)-like cell differentiation from monocytes plays a role in systemic anticancer immunity. In the present study, we generated recombinant full-length and N-terminally truncated REIC/Dkk-3 to characterize the biological activity of the protein. During the purification procedure, we identified a 17 kDa cysteine-rich stable product (C17-REIC) showing limited degradation. Further analysis showed that the C17-REIC domain was sufficient for the induction of DC-like cell differentiation from monocytes. Concomitant with the differentiation of DCs, the REIC/Dkk-3 protein induced the phosphorylation of glycogen synthase kinase 3β (GSK-3β) and signal transducers and activators of transcription (STAT) at a level comparable to that of granulocyte/macrophage colony-stimulating factor. In a mouse model of subcutaneous renal adenocarcinoma, intraperitoneal injection of full-length and C17-REIC proteins exerted anticancer effects in parallel with the activation of immunocompetent cells such as DCs and cytotoxic T lymphocytes in peripheral blood. Taken together, our results indicate that the stable cysteine-rich core region of REIC/Dkk-3 is responsible for the induction of anticancer immune responses. Because REIC/Dkk-3 is a naturally circulating serum protein, the upregulation REIC/Dkk-3 protein expression could be a promising option for cancer therapy.


The nutraceutical flavonoid luteolin inhibits ADAMTS-4 and ADAMTS-5 aggrecanase activities.
A disintegrin and metalloprotease with thrombospondin domains (ADAMTS)-4 (aggrecanase-1) and ADAMTS-5 (aggrecanase-2) are metalloproteases involved in articular cartilage degradation and represent potential therapeutic targets in arthritis treatment. We explore herein the ability of different natural compounds to specifically block the destructive action of these enzymes. Following a preliminary screening using carboxymethylated transferrin as substrate, we focused our interest on luteolin due to its inhibitory effect on ADAMTS-4 and ADAMTS-5 activities using aggrecan and fluorogenic peptides as substrates. However, matrix metalloproteinases (MMPs) activities on these substrates result less affected by this flavonoid. Moreover, incubation of mouse chondrogenic ATDC5 cells in the presence of luteolin clearly decreases the release of aggrecan fragments mediated by aggrecanases under the same conditions in which aggrecanolysis mediated by MMPs is detected. Additionally, glycosaminoglycan levels in culture medium of murine cartilage explants stimulated with interleukin-1-alpha plus retinoic acid are reduced by the presence of the flavonoid. This inhibition takes place through blockade of ADAMTS-mediated aggrecanolysis, while MMPs activity is not or poorly affected. These results suggest that luteolin could be employed as a prototypic modifying disease-agent to create new chondroprotective compounds aimed to specifically block the unwanted aggrecanase activities in arthritic diseases.


Accessing clinical services and retention in care following screening for hypertension and diabetes among Malawian adults: an urban/rural comparison.
Interventions to impact on the burden of chronic noncommunicable diseases, such as hypertension and diabetes, include screening of asymptomatic adults, but little is known about the subsequent course of clinical care. We report on the uptake of referral for clinical assessment and retention in care, following a large urban/rural population screening program in Malawi. Adult residents were screened for raised blood pressure and raised fasting blood glucose at a demographic surveillance site in rural Karonga District and in urban Area 25, Lilongwe with well supported chronic care clinics. Successful uptake was defined as presenting for clinical assessment within 6 weeks of referral, and nonattenders were followed at home. Logistic regression was used to examine association of uptake with demographic and clinical factors. Retention was assessed using survival analysis techniques. A total of 27 305 participants were screened for hypertension and diabetes between May 2013 and September 2015. Of these, 4075 (14.9%) were referred for suspected hypertension (3640), diabetes (172), or both (263). Among those referred, 2480 (60.9%), reported for clinical assessment. Factors associated with uptake of care included being female, rural residency, older age, unemployment, prior medication, and diabetes. Retention, for those enrolled in care following a formal clinical assessment, was associated with the final diagnosis following clinical assessment, rural residency, and older age. Screening for hypertension and diabetes identifies large numbers of individuals who need further clinical assessment, but strategies are needed to ensure better linkage and retention into care.


Removal of strontium from drinking water by conventional treatment and lime softening in bench-scale studies.
The United States Environmental Protection Agency Contaminant Candidate List 3 lists strontium as a contaminant for potential regulatory consideration in drinking water. Very limited data is available on strontium removal from drinking water and as a result, there is an immediate need for treatment information. The objective of this work is to evaluate the effectiveness of coagulation/filtration and lime-soda ash softening treatment methods to remove strontium from surface and ground waters. Coagulation/filtration jar test results on natural waters showed that conventional treatment with aluminum and iron coagulants were able to achieve only 12% and 5.9% strontium removal, while lime softening removed as high as 78% from natural strontium-containing ground water. Controlled batch experiments on synthetic water showed that strontium removal during the lime-soda ash softening was affected by pH, calcium concentration and dissolved inorganic carbon concentration. In all softening jar tests, the final strontium concentration was directly related to the initial strontium concentration and the removal of strontium was directly associated with calcium removal. Precipitated solids showed well-formed crystals or agglomerates of mixed solids, two polymorphs of calcium carbonate (vaterite and calcite), and strontianite, depending on initial water quality conditions. X-ray diffraction analysis suggested that strontium was likely incorporated in the calcium carbonate crystal lattice and was likely responsible for removal during lime softening.


Arene C-H functionalisation using a removable/modifiable or a traceless directing group strategy.
The use of coordinating moieties as directing groups for the functionalisation of aromatic carbon-hydrogen (C-H) bonds has become an efficient strategy for the selective construction of new carbon-carbon (C-C) and carbon-heteroatom (C-X) bonds in arenes. However many directing groups cannot be easily removed/modified from the products after C-H functionalisation, thus limiting the structural diversity of the products. This limitation can be overcome by employing removable/modifiable or traceless directing groups which can be easily attached to the starting materials and detached from the products. In this tutorial review, we give an overview of recent advances in this emerging field which have dramatically increased the synthetic applicability of C-H functionalisation processes.


A Q statistic with constant weights for assessing heterogeneity in meta-analysis.
The conventional Q statistic, using estimated inverse-variance (IV) weights, underlies a variety of problems in random-effects meta-analysis. In previous work on standardized mean difference and log-odds-ratio, we found superior performance with an estimator of the overall effect whose weights use only group-level sample sizes. The Q statistic with those weights has the form proposed by DerSimonian and Kacker. The distribution of this Q and the Q with IV weights must generally be approximated. We investigate approximations for those distributions, as a basis for testing and estimating the between-study variance (τ2 ). A simulation study, with mean difference as the effect measure, provides a framework for assessing accuracy of the approximations, level and power of the tests, and bias in estimating τ2 . Two examples illustrate estimation of τ2 and the overall mean difference. Use of Q with sample-size-based weights and its exact distribution (available for mean difference and evaluated by Farebrother's algorithm) provides precise levels even for very small and unbalanced sample sizes. The corresponding estimator of τ2 is almost unbiased for 10 or more small studies. This performance compares favorably with the extremely liberal behavior of the standard tests of heterogeneity and the largely biased estimators based on inverse-variance weights.


Risk factors of enterovirus 71 infection and associated hand, foot, and mouth disease/herpangina in children during an epidemic in Taiwan.
In 1998, an enterovirus 71 (EV71) epidemic in Taiwan was associated with hand, foot, and mouth disease (HFMD)/herpangina and involved 78 fatal cases. We measured EV71 seroprevalence rates before and after the epidemic and investigated risk factors associated with EV71 infection and illness. Neutralizing antibodies to EV71 were assayed for 539 people before the epidemic and 4619 people of similar ages after the epidemic. Questionnaires, which were completed during household interviews after the epidemic, solicited demographic variables, exposure history, and clinical manifestations. A total of 129 106 cases of HFMD were reported during the epidemic. Age-specific pre-epidemic EV71 seroprevalence rates were inversely related to age-specific periepidemic mortality rates (r = -0.82) or severe case rates (r = -0.93). Higher postepidemic EV71 seropositive rates among children who were younger than 3 years positively correlated with higher mortality rates in different areas (r = 0.88). After the epidemic, 51 (56%) of 91 younger siblings of elder siblings who were EV71-seropositive were EV71-seropositive; otherwise, 2.2% (4 of 186) of younger siblings were EV71-seropositive (matched odds ratio [OR]: 10; 95% confidence interval [CI]: 3.4-29). Stepwise multiple logistic regression revealed other factors associated with EV71 infection to be older age (adjusted OR: 2.5; 95% CI: 1.9-3.4), attendance at kindergartens/child care centers (adjusted OR: 1.8; 95% CI: 1.3-2.5), contact with HFMD/herpangina (adjusted OR: 1.6; 95% CI: 1.2-2.1), greater number of children in a family (adjusted OR: 1.4; 95% CI: 1.1-1.7), and rural residence (adjusted OR: 1.4; 95% CI: 1.2-1.6). Twenty-nine percent of preschool children who were infected with EV71 developed HFMD/herpangina. Younger age and contact with HFMD/herpangina were significant factors for the development of EV71-related HFMD/herpangina in these children. An increased incidence of EV71 infection in young children occurred more often in geographic areas with increased mortality rates. Intrafamilial and kindergarten transmissions among preschool children were major modes of disease transmission during the widespread EV71 epidemic in Taiwan in 1998.


Morpho-physiological criteria divide dentate gyrus interneurons into classes.
GABAergic inhibitory interneurons control fundamental aspects of neuronal network function. Their functional roles are assumed to be defined by the identity of their input synapses, the architecture of their dendritic tree, the passive and active membrane properties and finally the nature of their postsynaptic targets. Indeed, interneurons display a high degree of morphological and physiological heterogeneity. However, whether their morphological and physiological characteristics are correlated and whether interneuron diversity can be described by a continuum of GABAergic cell types or by distinct classes has remained unclear. Here we perform a detailed morphological and physiological characterization of GABAergic cells in the dentate gyrus, the input region of the hippocampus. To achieve an unbiased and efficient sampling and classification we used knock-in mice expressing the enhanced green fluorescent protein (eGFP) in glutamate decarboxylase 67 (GAD67)-positive neurons and performed cluster analysis. We identified five interneuron classes, each of them characterized by a distinct set of anatomical and physiological parameters. Cross-correlation analysis further revealed a direct relation between morphological and physiological properties indicating that dentate gyrus interneurons fall into functionally distinct classes which may differentially control neuronal network activity.


Theoretical study on activation and protonation of dinitrogen on cubane-type MIr3S4 clusters (M = V, Cr, Mn, Fe, Co, Ni, Cu, Mo, Ru, and W).
Density functional theory (DFT) calculations on cubane-type metal-sulfido clusters MIr(3)S(4) ligating N(2) (M = V, Cr, Mn, Fe, Co, Ni, Cu, Mo, Ru, and W) have been performed for the proposal of new clusters that can highly activate N(2) beyond the RuIr(3)S(4) cluster prepared by Mizobe and co-workers [Angew. Chem. Int. Ed. 2007, 46, 5431]. The degree of N(2) activation in the metal-N(2) complexes was evaluated based on the N-N bond distance and vibrational frequency and the gross atomic charge on N(2). The degree of N(2) activation strongly depends on the metal atoms at the N(2)-binding site, and the MoIr(3)S(4) and WIr(3)S(4) clusters exhibit significant N(2)-activation ability. The reactivity of the MIr(3)S(4)-N(2) complexes (M = Ru, Mo, and W) with a proton donor (lutidinium) has been discussed from a kinetic aspect by exploring a possible reaction pathway of proton transfer. The protonation of the Ru-N(2) complex would not occur due to a very high-activation barrier and to an instability of the Ru-NNH(+) complex, which is consistent with our present experimental result that the Ru-N(2) complex has not been protonated at room temperature. On the other hand, the protonation of the Mo-N(2) and W-N(2) complexes would proceed smoothly from DFT criteria. The result of calculations indicates that the Mo and W clusters are best suited for the protonation of N(2), which is the first step toward nitrogen fixation.


Distribution of Aliphatic Amines in CO, CV and CK Carbonaceous Chondrites and Relation to Mineralogy and Processing History.
The analysis of water-soluble organic compounds in meteorites provides valuable insights into the prebiotic synthesis of organic matter and the processes that occurred during the formation of the solar system. We investigated the concentration of aliphatic monoamines present in the hot acid-water extracts of the unaltered Antarctic carbonaceous chondrites DOM 08006 (CO3) and MIL 05013 (CO3), and the thermally altered meteorites Allende (CV3), LAP 02206 (CV3), GRA 06101 (CV3), ALH 85002 (CK4), and EET 92002 (CK5). We have also reviewed and assessed the petrologic characteristics of the meteorites studied here, to evaluate the effects of asteroidal processing on the abundance and molecular distributions of monoamines. The CO3, CV3, CK4, and CK5 meteorites studied here contain total concentrations of amines ranging from 1.2 to 4.0 nmol/g of meteorite; these amounts are one to three orders of magnitude below those observed in carbonaceous chondrites from the CI, CM and CR groups. The low amine abundances for CV and CK chondrites may be related to their extensive degree of thermal metamorphism and/or to their low original amine content. Although the CO3 meteorites DOM 08006 and MIL 05013 do not show signs of thermal and aqueous alteration, their monoamine contents are comparable to those observed in moderately/extensively thermally altered CV3, CK4, and CK5 carbonaceous chondrites. The low content of monoamines in pristine CO carbonaceous chondrites suggests that the initial amounts, and not asteroidal processes, play a dominant role in the content of monoamines in carbonaceous chondrites. The primary monoamines, methylamine, ethylamine and n-propylamine constitute the most abundant amines in the CO3, CV3, CK4, and CK5 meteorites studied here. Contrary to the predominance of n-ω-amino acid isomers in CO3 and thermally altered meteorites, there appears to be no preference for the larger n-α-amines.


Fluconazole assists berberine to kill fluconazole-resistant Candida albicans.
It was found in our previous study that berberine (BBR) and fluconazole (FLC) used concomitantly exhibited a synergism against FLC-resistant Candida albicans in vitro. The aim of the present study was to clarify how BBR and FLC worked synergistically and the underlying mechanism. Antifungal time-kill curves indicated that the synergistic effect of the two drugs was BBR dose dependent rather than FLC dose dependent. In addition, we found that BBR accumulated in C. albicans cells, especially in the nucleus, and resulted in cell cycle arrest and significant change in the transcription of cell cycle-related genes. Besides BBR, other DNA intercalators, including methylene blue, sanguinarine, and acridine orange, were all found to synergize with FLC against FLC-resistant C. albicans. Detection of intracellular BBR accumulation by fluorescence measurement showed that FLC played a role in increasing intracellular BBR concentration, probably due to its effect in disrupting the fungal cell membrane. Similar to the case with FLC, other antifungal agents acting on the cell membrane were able to synergize with BBR. Interestingly, we found that the efflux of intracellular BBR was FLC independent but strongly glucose dependent and associated with the drug efflux pump Cdr2p. These results suggest that BBR plays a major antifungal role in the synergism of FLC and BBR, while FLC plays a role in increasing the intracellular BBR concentration.


National, regional, and state-level all-cause and cause-specific under-5 mortality in India in 2000-15: a systematic analysis with implications for the Sustainable Development Goals.
India had the largest number of under-5 deaths of all countries in 2015, with substantial subnational disparities. We estimated national and subnational all-cause and cause-specific mortality among children younger than 5 years annually in 2000-15 in India to understand progress made and to consider implications for achieving the Sustainable Development Goal (SDG) child survival targets. We used a multicause model to estimate cause-specific mortality proportions in neonates and children aged 1-59 months at the state level, with causes of death grouped into pneumonia, diarrhoea, meningitis, injury, measles, congenital abnormalities, preterm birth complications, intrapartum-related events, and other causes. AIDS and malaria were estimated separately. The model was based on verbal autopsy studies representing more than 100 000 neonatal deaths globally and 16 962 deaths among children aged 1-59 months at the subnational level in India. By applying these proportions to all-cause deaths by state, we estimated cause-specific numbers of deaths and mortality rates at the state, regional, and national levels. In 2015, there were 25·121 million livebirths in India and 1·201 million under-5 deaths (under-5 mortality rate 47·81 per 1000 livebirths). 0·696 million (57·9%) of these deaths occurred in neonates. There were disparities in child mortality across states (from 9·7 deaths [Goa] to 73·1 deaths [Assam] per 1000 livebirths) and regions (from 29·7 deaths [the south] to 63·8 deaths [the northeast] per 1000 livebirths). Overall, the leading causes of under-5 deaths were preterm birth complications (0·330 million [95% uncertainty range 0·279-0·367]; 27·5% of under-5 deaths), pneumonia (0·191 million [0·168-0·219]; 15·9%), and intrapartum-related events (0·139 million [0·116-0·165]; 11·6%), with cause-of-death distributions varying across states and regions. In states with very high under-5 mortality, infectious-disease-related causes (pneumonia and diarrhoea) were among the three leading causes, whereas the three leading causes were all non-communicable in states with very low mortality. Most states had a slower decline in neonatal mortality than in mortality among children aged 1-59 months. Ten major states must accelerate progress to achieve the SDG under-5 mortality target, while 17 are not on track to meet the neonatal mortality target. Efforts to reduce vaccine-preventable deaths and to reduce geographical disparities should continue to maintain progress achieved in 2000-15. Enhanced policies and programmes are needed to accelerate mortality reduction in high-burden states and among neonates to achieve the SDG child survival targets in India by 2030. Bill & Melinda Gates Foundation.


Three distinct point mutations in the factor IX gene of three Japanese CRM+ hemophilia B patients (factor IX BMNagoya 2, factor IX Nagoya 3 and 4).
Enzymatic DNA amplification and complete sequence analysis were used to investigate human factor IX coding sequences in three CRM+ hemophilia B patients. In a patient with severe hemophilia B and a markedly prolonged ox-brain prothrombin time, a C to T transition in exon VI changed the codon for Arg180 to Trp (factor IX BMNagoya 2). This mutation would impair the cleavage by factor XIa required for activation of the zymogen. In a patient with mild hemophilia B, a G to A transition in exon VI changed the codon for Arg145 to His(factor IX Nagoya 3). This substitution also would be predicted to preclude the cleavage of factor IX by factor XIa at this peptide bond (Arg145-Ala146). Furthermore, this point mutation creates a new NlaIII restriction site which provides a quick and reliable method for carrier detection in the affected family members. A patient with severe hemophilia B (factor IX Nagoya 4) had a G to A transition in exon II changing the codon for Glu21 to Lys. This novel point mutation is assumed to impair the function of factor IX by disrupting the calcium binding of factor IX.


Comparison of mesenchymal stem cells from adipose tissue and bone marrow for ischemic stroke therapy.
Transplantation of mesenchymal stromal cells (MSC) derived from bone marrow (BM) or adipose tissue is expected to become a cell therapy for stroke. The present study compared the therapeutic potential of adipose-derived stem cells (ASC) with that of BM-derived stem cells (BMSC) in a murine stroke model. ASC and BMSC were isolated from age-matched C57BL/6J mice. These MSC were analyzed for growth kinetics and their capacity to secrete trophic factors and differentiate toward neural and vascular cell lineages in vitro. For in vivo study, ASC or BMSC were administrated intravenously into recipient mice (1 × 10(5) cells/mouse) soon after reperfusion following a 90-min middle cerebral artery occlusion. Neurologic deficits, the degree of infarction, expression of factors in the brain, and the fate of the injected cells were observed. ASC showed higher proliferative activity with greater production of vascular endothelial cell growth factor (VEGF) and hepatocyte growth factor (HGF) than BMSC. Furthermore, in vitro conditions allowed ASC to differentiate into neural, glial and vascular endothelial cells. ASC administration showed remarkable attenuation of ischemic damage, although the ASC were not yet fully incorporated into the infarct area. Nonetheless, the expression of HGF and angiopoietin-1 in ischemic brain tissue was significantly increased in ASC-treated mice compared with the BMSC group. Compared with BMSC, ASC have great advantages for cell preparation because of easier and safer access to adipose tissue. Taken together, our findings suggest that ASC would be a more preferable source for cell therapy for brain ischemia than BMSC.


Nitric Oxide and Reactive Oxygen Species Mediate Metabolic Changes in Barley Seed Embryo during Germination.
The levels of nitric oxide (NO) and reactive oxygen species (ROS), ATP/ADP ratios, reduction levels of ascorbate and glutathione, expression of the genes encoding proteins involved in metabolism of NO and activities of the enzymes involved in fermentation and in metabolism of NO and ROS were studied in the embryos of germinating seeds of two barley (Hordeum vulgare L.) cultivars differing in dormancy level. The level of NO production continuously increased after imbibition while the level of nitrosylated SH-groups in proteins increased. This corresponded to the decrease of free SH-groups in proteins. At early stage of germination (0-48 h post imbibition) the genes encoding class 1 phytoglobin (the protein scavenging NO) and S-nitrosoglutathione reductase (scavenging S-nitrosoglutathione) were markedly expressed. More dormant cultivar exhibited lower ATP/ADP and ascorbate/dehydroascorbate ratios and lower lactate and alcohol dehydrogenase activities, while the production of NO and nitrosylation of proteins was higher as compared to the non-dormant cultivar. The obtained data indicate that at the onset of germination NO is actively generated causing nitrosylation of SH-groups and a switch from respiration to fermentation. After radicle protrusion the metabolism changes in a more reducing type as recorded by ratio of reduced and oxidized glutathione and ascorbate. The turnover of NO by the scavenging systems (phytoglobin, S-nitrosoglutathione reductase and interaction with ROS) might contribute to the maintenance of redox and energy balance of germinating seeds and lead to alleviation of dormancy.


Parkin Mediates Cannabidiol Prevention of Amyloid-Beta-Induced Senescence in Human Astrocytes.
Introduction: As aging is the leading risk factor for Alzheimer's disease (AD), ablation of senescent cells is a promising therapeutic approach to prevent AD. It is known that astrocytes lose their ability to maintain a healthy brain environment when aging. Studies have recently shown that cannabidiol (CBD) provides a promising therapeutic avenue for AD; however, if or how CBD prevents astrocyte aging is not known. Materials and Methods: In this study, human astrocytes were employed to measure amyloid-beta (Aβ)-induced senescence features, including senescence-associated β-galactosidase (SA-β-gal), p16INK4A, p21WAF1, and p53. The effects of CBD on the production of mitochondrial dysfunction and mitophagy pathway were measured by Western blot and fluorescence assay. Caenorhabditis elegans was used as in vivo AD model to investigate the effects of CBD on life span and health span. All experimental procedures were approved by the Human Research Ethics Committee, University of Wollongong, Australia. Results: In human astrocytes, we show that treatment with Aβ, an endogenous pathogenic agent of AD, results in an increase in the percentage of SA-β-gal-positive cells and induces mitochondrial reactive oxygen species (ROS). However, CBD treatment protects from Aβ-induced senescence. Furthermore, the anti-senescence and anti-apoptotic activities of CBD were observed to be mediated through the protective effect of Parkin-dependent mitophagy. In C. elegans, we used the transgenic GRU102 strain, which expresses the human Aβ peptide, and found that CBD treatment extended life span, improved pumping rate, and decreased mitochondrial ROS. Conclusion and Significance: Our results demonstrate that CBD prevents the human astrocyte senescence induced by Aβ by a mechanism involving the Parkin-mediated mitophagy pathway. Our findings support the new therapeutic avenues of CBD for the treatment of AD patients.


Restriction associated DNA-genotyping at multiple spatial scales in Arabidopsis lyrata reveals signatures of pathogen-mediated selection.
Genome scans based on outlier analyses have revolutionized detection of genes involved in adaptive processes, but reports of some forms of selection, such as balancing selection, are still limited. It is unclear whether high throughput genotyping approaches for identification of single nucleotide polymorphisms have sufficient power to detect modes of selection expected to result in reduced genetic differentiation among populations. In this study, we used Arabidopsis lyrata to investigate whether signatures of balancing selection can be detected based on genomic smoothing of Restriction Associated DNA sequencing (RAD-seq) data. We compared how different sampling approaches (both within and between subspecies) and different background levels of polymorphism (inbreeding or outcrossing populations) affected the ability to detect genomic regions showing key signatures of balancing selection, specifically elevated polymorphism, reduced differentiation and shifts towards intermediate allele frequencies. We then tested whether candidate genes associated with disease resistance (R-gene analogs) were detected more frequently in these regions compared to other regions of the genome. We found that genomic regions showing elevated polymorphism contained a significantly higher density of R-gene analogs predicted to be under pathogen-mediated selection than regions of non-elevated polymorphism, and that many of these also showed evidence for an intermediate site-frequency spectrum based on Tajima's D. However, we found few genomic regions that showed both elevated polymorphism and reduced FST among populations, despite strong background levels of genetic differentiation among populations. This suggests either insufficient power to detect the reduced population structure predicted for genes under balancing selection using sparsely distributed RAD markers, or that other forms of diversifying selection are more common for the R-gene analogs tested. Genome scans based on a small number of individuals sampled from a wide range of populations were sufficient to confirm the relative scarcity of signatures of balancing selection across the genome, but also identified new potential disease resistance candidates within genomic regions showing signatures of balancing selection that would be strong candidates for further sequencing efforts.


Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation.
We sought to compare the efficacy and safety of dronedarone versus amiodarone for the prevention of recurrent atrial fibrillation (AF). Dronedarone is a noniodinated amiodarone congener developed to maintain sinus rhythm. Few data are available to directly compare the efficacy and safety of dronedarone versus amiodarone. We conducted a systematic overview of all randomized controlled trials in which the authors evaluated dronedarone or amiodarone for the prevention of AF. The effect of amiodarone versus dronedarone was summarized by the use of indirect comparison meta-analysis and normal logistic meta-regression models. We identified 4 placebo-controlled trials of dronedarone, 4 placebo-controlled trials of amiodarone, and 1 trial of dronedarone versus amiodarone. By using random-effects modeling, we found that there was a significant estimated reduction in recurrent AF with amiodarone versus placebo (odds ratio [OR]: 0.12; 95% confidence interval [CI]: 0.08 to 0.19) but not dronedarone versus placebo (OR: 0.79; 95% CI: 0.33 to 1.87). A normal logistic regression model incorporating all trial evidence found amiodarone superior to dronedarone (OR: 0.49; 95% CI: 0.37 to 0.63; p < 0.001) for the prevention of recurrent AF. In contrast, these models also found a trend toward greater all-cause mortality (OR: 1.61; 95% CI: 0.97 to 2.68; p = 0.066) and greater overall adverse events requiring drug discontinuation with amiodarone versus dronedarone (OR: 1.81; 95% CI: 1.33 to 2.46; p < 0.001). Dronedarone is less effective than amiodarone for the maintenance of sinus rhythm, but has fewer adverse effects. For every 1,000 patients treated with dronedarone instead of amiodarone, we estimate approximately 228 more recurrences of AF in exchange for 9.6 fewer deaths and 62 fewer adverse events requiring discontinuation of drug.


360 MHz PMR studies on the involvement of the Y-nucleoside in the conformation of 2'-OMeGpApApYpAppsi from torula yeast tRNAphe.
360 MHz measurements of chemical shifts, 3J1'-2', and T1 as a function of temperature for various protons of the hexanucleotide 2'-OMeGpApApYpAppsi from torula yeast tRNAphe have revealed a unique involvement of the Yt base in the structure and conformation of this oligonucleotide. Whereas the adenosine residues in the anticodon triplet are relatively stable to temperature increase, the Yt readily undergoes destacking and a change in ribose conformation. The destacking most likely involves a torsional displacement of the Yt base occasioned by a rotation of the phosphate-ribose backbone. The possible relevance of this unusual behavior to the influence of the Yt residue in tRNA function in protein biosynthesis is discussed.


Quantitative assessments of the distinct contributions of polypeptide backbone amides versus side chain groups to chain expansion via chemical denaturation.
In aqueous solutions with high concentrations of chemical denaturants such as urea and guanidinium chloride (GdmCl) proteins expand to populate heterogeneous conformational ensembles. These denaturing environments are thought to be good solvents for generic protein sequences because properties of conformational distributions align with those of canonical random coils. Previous studies showed that water is a poor solvent for polypeptide backbones, and therefore, backbones form collapsed globular structures in aqueous solvents. Here, we ask if polypeptide backbones can intrinsically undergo the requisite chain expansion in aqueous solutions with high concentrations of urea and GdmCl. We answer this question using a combination of molecular dynamics simulations and fluorescence correlation spectroscopy. We find that the degree of backbone expansion is minimal in aqueous solutions with high concentrations of denaturants. Instead, polypeptide backbones sample conformations that are denaturant-specific mixtures of coils and globules, with a persistent preference for globules. Therefore, typical denaturing environments cannot be classified as good solvents for polypeptide backbones. How then do generic protein sequences expand in denaturing environments? To answer this question, we investigated the effects of side chains using simulations of two archetypal sequences with amino acid compositions that are mixtures of charged, hydrophobic, and polar groups. We find that side chains lower the effective concentration of backbone amides in water leading to an intrinsic expansion of polypeptide backbones in the absence of denaturants. Additional dilution of the effective concentration of backbone amides is achieved through preferential interactions with denaturants. These effects lead to conformational statistics in denaturing environments that are congruent with those of canonical random coils. Our results highlight the role of side chain-mediated interactions as determinants of the conformational properties of unfolded states in water and in influencing chain expansion upon denaturation.


A penny for your thoughts! patterns of fMRI activity reveal the content and the spatial topography of visual mental images.
Visual mental imagery is a complex process that may be influenced by the content of mental images. Neuropsychological evidence from patients with hemineglect suggests that in the imagery domain environments and objects may be represented separately and may be selectively affected by brain lesions. In the present study, we used functional magnetic resonance imaging (fMRI) to assess the possibility of neural segregation among mental images depicting parts of an object, of an environment (imagined from a first-person perspective), and of a geographical map, using both a mass univariate and a multivariate approach. Data show that different brain areas are involved in different types of mental images. Imagining an environment relies mainly on regions known to be involved in navigational skills, such as the retrosplenial complex and parahippocampal gyrus, whereas imagining a geographical map mainly requires activation of the left angular gyrus, known to be involved in the representation of categorical relations. Imagining a familiar object mainly requires activation of parietal areas involved in visual space analysis in both the imagery and the perceptual domain. We also found that the pattern of activity in most of these areas specifically codes for the spatial arrangement of the parts of the mental image. Our results clearly demonstrate a functional neural segregation for different contents of mental images and suggest that visuospatial information is coded by different patterns of activity in brain areas involved in visual mental imagery.


Brevibacillus sediminis sp. nov., isolated from a hot spring.
Strain YIM 78300T, a novel Gram-stain-positive, moderately thermophilic, endospore-forming, rod-shaped, motile bacterium, was recovered from the sediment of a hot spring in the Tagejia Geothermal Field, Angren, Tibet province, western China. Optimum growth was observed at 50-55 °C, at pH 7.0 and with 0-1.5 % (w/v) NaCl. Phylogenetic analysis of the 16S rRNA gene sequence of strain YIM 78300T indicated that it belongs to the genus Brevibacillus. Similarity levels between the 16S rRNA gene sequences of the new isolate and those of the type strains of Brevibacillus members were 96.9-96.3 %; highest sequence similarity was with Brevibacillus thermoruber DSM 7064T. The predominant menaquinone was MK-7 and the major cellular fatty acids were iso-C15 : 0 and iso-C17 : 0. The major polar lipids were phosphatidyl-N-methylethanolamine, phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, two unidentified phospholipids, an unidentified aminophospholipid and two unidentified polar lipids. The G+C content of the genomic DNA of strain YIM 78300T was 57.9 mol%. Based on phylogenetic analyses, and physiological and biochemical characteristics, strain YIM 78300T is considered to represent a novel species of the genus Brevibacillus, for which the name Brevibacillus sediminis sp. nov. is proposed. The type strain is YIM 78300T ( = DSM 29928T = CPCC 100738T).


Dentinal Tubule Penetration of Tricalcium Silicate Sealers.
The treatments for which mineral trioxide aggregate (MTA)-based materials can be used in dentistry are expanding. Smaller particle size and easier handling properties have allowed the advent of tricalcium silicate sealers including EndoSequence BC Sealer (Brasseler USA, Savannah, GA), QuickSet2 (Avalon Biomed, Bradenton, FL), NeoMTA Plus (Avalon Biomed), and MTA Fillapex (Angelus, Londrina, Brazil). The objective of this study was to measure the tubule penetration with these sealers using continuous wave (CW) and single-cone (SC) obturation techniques. Eighty single-rooted teeth were randomly divided into 8 groups of 10 and obturated with 1 of the previously mentioned sealers mixed with trace amounts of rhodamine using either the CW or SC technique. Teeth were sectioned at 1 mm and 5 mm from the apex and examined under a confocal laser microscope. The percentage of sealer penetration and the maximum sealer penetration were measured. The tricalcium silicate sealers penetrated tubules as deep as 2000 μm (2 mm). The percentage of sealer penetration was much higher 5 mm from the apex, with many specimens having 100% penetration for both SC and warm vertical techniques. MTA Fillapex, a resin-based sealer with less than 20% MTA particles, had significantly greater tubule penetration with a warm vertical technique versus the SC technique at the 1-mm level. Within the limitations of this study, the CW and SC techniques produced similar tubule penetration at both the 1-mm and the 5-mm level with the tricalcium silicate sealers BC Sealer, QuickSet2, and NeoMTA Plus.


Early determinants of right and left ventricular output in ventilated preterm infants.
One hundred and twenty ventilated preterm infants, birthweight < 1500 g, were examined within the first 36 hours with colour Doppler echocardiography, to determine the cardiorespiratory influences on right (RVO) and left ventricular output (LVO). Forty nine of these infants had three further daily scans. Measurements included left ventricular (LV) ejection fraction, Doppler determination of RVO and LVO, and ductal and interatrial shunt direction, velocity and colour Doppler diameter. Infants were grouped by respiratory disease severity: mild, mean FIO2 in first 24 hours < 0.5; moderate/severe, mean FIO2 < 0.5; and fatal, death resulting directly from acute respiratory distress. In the early studies ventricular outputs varied widely (RVO: 62-412 ml/kg/minute, LVO: 75-505 ml/kg/minute). The incidence of low ventricular outputs (< 150 ml/kg/minute) increased with worsening respiratory disease. The incidence of low RVO in the mild group was 19%, in the moderate/severe group 42%, and in the fatal group 85%. More infants had a low RVO than a low LVO, reflecting the impact of ductal shunting. Ductal and atrial shunting was predominantly left to right except in those with fatal respiratory disease. In those studied longitudinally, RVO and LVO increased with age and low outputs were not seen after day 3. Multilinear regression analyses, with RVO as the dependent variable, revealed increasing LVO and atrial shunt diameter as significant positive influences and increasing ductal shunt diameter and mean airway pressure as a significant negative influence. With LVO as the dependent variable, increasing RVO, ductal shunt diameter, and age were significant positive influences and increasing atrial shunt diameter was a significant negative influence. Low ventricular outputs are more common with worsening respiratory disease. Mean airway pressure and ductal shunting are two negative influences on ventricular outputs over which there is some therapeutic control.


X-ray Absorption Spectroscopic Investigation of Trace Vanadium Sites in Coal.
X-ray absorption spectroscopy was used to probe the chemical and structural environment of vanadium in coal. It was found that vanadium exists in at least two environments, in both of which it was coordinated to oxygens. There was no evidence of vanadium in nitrogen (porphyrin) or sulfide environments. It was also found that the vanadium environments in the raw coal did not survive unchanged in a liquefaction process. These findings have implications for coal cleaning processes and for trace element release into the liquefaction process stream.


Disorder specific and trans-diagnostic case conceptualisation.
Case conceptualisation is the process of integrating the unique experience of the individual with psychological theory and is often described as a central process in effective therapy. Hence, a key question facing a clinician working from a cognitive behavioural perspective is which theory should be chosen as the basis of the conceptualisation with a particular client? We address this question by first considering the strengths and limitations of the disorder specific and trans-diagnostic approaches. From this, the differences between the approaches are framed as a conundrum or puzzle that is solved through a principle based approach to case conceptualisation that allows clinicians to individualise therapy by selecting and incorporating the most appropriate theory and research. Furthermore, by considering how to achieve lasting improvement for the client we emphasise incorporating client strengths and resilience into both disorder specific and trans-diagnostic approaches. To achieve this we necessarily extend beyond consideration of models of disorders, and draw on models of wellbeing, and resilience, and by doing so require theoretical accounts not only of disorders but also of resilience.


Cerebral specialization and interhemispheric communication: does the corpus callosum enable the human condition?
The surgical disconnection of the cerebral hemispheres creates an extraordinary opportunity to study basic neurological mechanisms: the organization of the sensory and motors systems, the cortical representation of the perceptual and cognitive processes, the lateralization of function, and, perhaps most importantly, how the divided brain yields clues to the nature of conscious experience. Studies of split-brain patients over the last 40 years have resulted in numerous insights into the processes of perception, attention, memory, language and reasoning abilities. When the constellation of findings is considered as a whole, one sees the cortical arena as a patchwork of specialized processes. When this is considered in the light of new studies on the lateralization of functions, it becomes reasonable to suppose that the corpus callosum has enabled the development of the many specialized systems by allowing the reworking of existing cortical areas while preserving existing functions. Thus, while language emerged in the left hemisphere at the cost of pre-existing perceptual systems, the critical features of the bilaterally present perceptual system were spared in the opposite half-brain. By having the callosum serve as the great communication link between redundant systems, a pre-existing system could be jettisoned as new functions developed in one hemisphere, while the other hemisphere could continue to perform the previous functions for both half-brains. Split-brain studies have also revealed the complex mosaic of mental processes that participate in human cognition. And yet, even though each cerebral hemisphere has its own set of capacities, with the left hemisphere specialized for language and speech and major problem-solving capacities and the right hemisphere specialized for tasks such as facial recognition and attentional monitoring, we all have the subjective experience of feeling totally integrated. Indeed, even though many of these functions have an automatic quality to them and are carried out by the brain prior to our conscious awareness of them, our subjective belief and feeling is that we are in charge of our actions. These phenomena appear to be related to our left hemisphere's interpreter, a device that allows us to construct theories about the relationship between perceived events, actions and feelings.


Viral neuroinvasion and encephalitis induced by lipopolysaccharide and its mediators.
The present study was designed to test the effect of bacterial endotoxin on penetration of viruses into the central nervous system (CNS). As a model we used two neurovirulent viruses that lack neuroinvasive capacity: West Nile virus-25 (WN-25) and neuroadapted Sindbis virus (SVN). Administration of lipopolysaccharide (LPS, 100 micrograms/mouse) to CD-1 mice, followed by WN-25 inoculation resulted in 83% encephalitis and death, compared with less than 5% in controls. The results in SVN-inoculated CD-1 mice were quite similar. LPS-treated mice suffered 62% mortality compared with 6% in the nontreated group. No changes in viral neuroinvasiveness were demonstrated in viruses isolated from brains of encephalitic mice, suggesting that neuroinvasion is not due to a selection process for an invasive variant, but to direct penetration of the viruses through the blood-brain barrier (BBB). LPS did not induce WN-25 encephalitis in LPS-insensitive C3H/HeJ mice, compared with 100% neuroinvasion in C3H/HeB mice. Induction of neuroinvasion could be transferred to C3H/HeJ mice by transfusion with serum obtained from LPS-treated, LPS-responsive mice. Passive immunization of CD-1 mice with anti-mTNF antibodies before LPS administration did not prevent LPS-induced WN-25 encephalitis. Furthermore, neutralization of tumor necrosis factor activity in the serum of LPS-treated mice did not abolish its activity, and transfusion-associated encephalitis was observed after the administration of the neutralized serum with WN-25. We suggest that LPS can contribute to virus penetration from the blood into the CNS, a process which turns a mild viral infection into a severe lethal encephalitis. This effect is mediated by soluble factors, and is probably achieved by injury to cerebral microvascular endothelium and modulation of BBB permeability.


Lafutidine versus lansoprazole in combination with clarithromycin and amoxicillin for one versus two weeks for Helicobacter pylori eradication in Korea.
Lafutidine is a novel H(2)-receptor antagonist with gastroprotective activity that includes enhancement of gastric mucosal blood flow. The aim of the present study was to test the efficacy of 7- or 14-day lafutidine-clarithromycin-amoxicillin therapy versus a lansoprazole-based regimen for Helicobacter pylori eradication. Four hundred and sixty-three patients with H. pylori-infected peptic ulcer disease were randomized to one of four regimens: (1) lafutidine (20 mg b.i.d.), clarithromycin (500 mg b.i.d.) and amoxicillin (1000 mg b.i.d.) for 7 days (the 7LFT group) or (2) for 14 days (the 14LFT group); (3) lansoprazole (30 mg b.i.d.), clarithromycin (500 mg b.i.d.), and amoxicillin (1000 mg b.i.d.) for 7 days (the 7LPZ group); or (4) for 14 days (the 14LPZ group). The eradication rates, drug compliance, and adverse effects among the four regimens were compared. The eradication rates by the intention-to-treat and per-protocol analyses in the 7LFT and 7LPZ groups were 76.5% and 81.6%, and 76.9% and 82.0% (p = .94 and .95), respectively. The eradication rates by intention-to-treat and per-protocol analyses in the 14LFT and 14LPZ groups were 78.2% and 82.2%, and 80.4% and 85.9% (p = .70 and .49), respectively. The treatment duration for 7 days or 14 days did not affect the eradication rates. In addition, the adverse effect rates and discontinuation rates were similar among the four groups. Furthermore, the ulcer cure rate and symptom response rate were similar in the lafutidine and lansoprazole groups. The results of this study showed that lafutidine-clarithromycin-amoxicillin therapy was a safe and effective as lansoprazole-based triple therapy for the eradication rate of H. pylori, and could be considered as an additional treatment option.


Acute seizures attributable to falciparum malaria in an endemic area on the Kenyan coast.
Falciparum malaria is an important cause of acute symptomatic seizures in children admitted to hospitals in sub-Saharan Africa, and these seizures are associated with neurological disabilities and epilepsy. However, it is difficult to determine the proportion of seizures attributable to malaria in endemic areas since a significant proportion of asymptomatic children have malaria parasitaemia. We studied children aged 0-13 years who had been admitted with a history of seizures to a rural Kenyan hospital between 2002 and 2008. We examined the changes in the incidence of seizures with the reduction of malaria. Logistic regression was used to model malaria-attributable fractions for seizures (the proportion of seizures caused by malaria) to determine if the observed decrease in acute symptomatic seizures was a measure of seizures that are attributable to malaria. The overall incidence of acute symptomatic seizures over the period was 651/100,000/year (95% confidence interval 632-670) and it was 400/100,000/year (95% confidence interval 385-415) for acute complex symptomatic seizures (convulsive status epilepticus, repetitive or focal) and 163/100,000/year (95% confidence interval 154-173) for febrile seizures. From 2002 to 2008, the incidence of all acute symptomatic seizures decreased by 809/100,000/year (69.2%) with 93.1% of this decrease in malaria-associated seizures. The decrease in the incidence of acute complex symptomatic seizures during the period was 111/100,000/year (57.2%) for convulsive status epilepticus, 440/100,000/year (73.7%) for repetitive seizures and 153/100,000/year (80.5%) for focal seizures. The adjusted malaria-attributable fractions for seizures with parasitaemia were 92.9% (95% confidence interval 90.4-95.1%) for all acute symptomatic seizures, 92.9% (95% confidence interval 89.4-95.5%) for convulsive status epilepticus, 93.6% (95% confidence interval 90.9-95.9%) for repetitive seizures and 91.8% (95% confidence interval 85.6-95.5%) for focal seizures. The adjusted malaria-attributable fractions for seizures in children above 6 months of age decreased with age. The observed decrease in all acute symptomatic seizures (809/100 000/year) was similar to the predicted decline (794/100,000/year) estimated by malaria-attributable fractions at the beginning of the study. In endemic areas, falciparum malaria is the most common cause of seizures and the risk for seizures in malaria decreases with age. The reduction in malaria has decreased the burden of seizures that are attributable to malaria and this could lead to reduced neurological disabilities and epilepsy in the area.


Hospital-wide multidisciplinary, multimodal intervention programme to reduce central venous catheter-associated bloodstream infection.
Central line-associated bloodstream infection (CLABSI) is the major complication of central venous catheters (CVC). The aim of the study was to test the effectiveness of a hospital-wide strategy on CLABSI reduction. Between 2008 and 2011, all CVCs were observed individually and hospital-wide at a large university-affiliated, tertiary care hospital. CVC insertion training started from the 3rd quarter and a total of 146 physicians employed or newly entering the hospital were trained in simulator workshops. CVC care started from quarter 7 and a total of 1274 nurses were trained by their supervisors using a web-based, modular, e-learning programme. The study included 3952 patients with 6353 CVCs accumulating 61,366 catheter-days. Hospital-wide, 106 patients had 114 CLABSIs with a cumulative incidence of 1.79 infections per 100 catheters. We observed a significant quarterly reduction of the incidence density (incidence rate ratios [95% confidence interval]: 0.92 [0.88-0.96]; P<0.001) after adjusting for multiple confounders. The incidence densities (n/1000 catheter-days) in the first and last study year were 2.3/1000 and 0.7/1000 hospital-wide, 1.7/1000 and 0.4/1000 in the intensive care units, and 2.7/1000 and 0.9/1000 in non-intensive care settings, respectively. Median time-to-infection was 15 days (Interquartile range, 8-22). Our findings suggest that clinically relevant reduction of hospital-wide CLABSI was reached with a comprehensive, multidisciplinary and multimodal quality improvement programme including aspects of behavioural change and key principles of good implementation practice. This is one of the first multimodal, multidisciplinary, hospital-wide training strategies successfully reducing CLABSI.


Transfection in the third dimension.
An understanding of parameters that modulate gene transfer in 3-D will assist in the formation of gene delivery systems and scaffolds, which can mediate efficient non-viral delivery for guiding in vivo tissue regeneration and therapy. We have previously demonstrated the cell area and length, integrin expression, and RhoGTPase mediated signalling to be pivotal parameters that guide gene transfer to mouse mesenchymal stem cells (mMSCs) cultured in 2-D and are modulated by ECM proteins. In this study, we were interested in determining if cationic polymer mediated gene transfer to cells seeded in 3-D would occur through different mechanisms as compared to those seeded in 2-D. In particular, we examined the endocytosis pathways used to internalize polyplexes, and the role of cytoskeletal dynamics and RhoGTPases in non-viral gene transfer for cells seeded in 2-D and 3-D. Inhibition of clathrin- and caveolae-mediated endocytosis resulted in a more drastic decrease in overall transgene expression for cells seeded in 3-D than for those in 2-D. In addition, polyplex internalization was only significantly decreased in 3-D when clathrin-mediated endocytosis was inhibited, while caveolae-mediated endocytosis inhibition for cells seeded in 2-D resulted in the strongest polyplex internalization inhibition. Actin and microtubule polymerization affected 2-D and 3-D transfection differently. Microtubule depolymerization enhanced transgene expression in 2-D, but inhibited transgene expression in 3-D. Lastly, inhibition of RhoGTPases also affected 2-D and 3-D transfection differently. The inhibition of ROCK effectors resulted in a decrease of transgene expression and internalization for cells seeded in 3-D, but not in 2-D, and the inhibition of the effector PAK1 resulted in an increase of transgene expression for both 2-D and 3-D. Overall, our study suggests that the process of gene transfer occurs through different mechanisms for cells seeded in 2-D compared to those seeded in 3-D.


Microfluidic device to study flow-free chemotaxis of swimming cells.
Microfluidic devices have been used in the last two decades to study in vitro cell chemotaxis, but few existing devices generate gradients in flow-free conditions. Flow can bias cell directionality of adherent cells and precludes the study of swimming cells like naïve T lymphocytes, which only migrate in a non-adherent fashion. We developed two devices that create stable, flow-free, diffusion-based gradients and are adapted for adherent and swimming cells. The flow-free environment is achieved by using agarose gel barriers between a central channel with cells and side channels with chemoattractants. These barriers insulate cells from injection/rinsing cycles of chemoattractants, they dampen residual drift across the device, and they allow co-culture of cells without physical interaction, to study contactless paracrine communication. Our devices were used here to investigate neutrophil and naïve T lymphocyte chemotaxis.


Architecture-controlled "SMART" Calix[6]arene self-assemblies in aqueous solution.
Self-assemblies of a calix[6]arene (1) functionalized at the small rim by three imidazolyl arms and at the large rim by three hydrophilic sulfonato groups have been studied in water. Transmission electron microscopy, atomic force microscopy, and in situ dynamic light scattering showed that 1 forms multilamellar vesicles at a concentration equal to or higher than 10(-4) M. At pH 7.8 and 10(-4) M, the multilamellar vesicles present a relatively large polydispersity (50-250 nm in diameter). However, after sonication unilamellar vesicles of much lower polydispersity and smaller size are obtained. The impact of the pH and the presence of Ag+ ions have also been investigated. Whereas increasing the pH led to the formation of giant vesicles (450 nm), monodisperse vesicules of 50 nm were obtained at a pH (6.5) that is only slightly higher than the pKa of the tris(imidazole) core of 1. Most interestingly, in the presence of silver ions, micelles (2.5 nm large) were obtained instead of vesicles. These observations are attributable to the imidazole core in 1 that is not only sensitive to the presence of protons but also can bind a silver cation. The resulting geometrical change in the monomeric units triggers the collapse of the vesicles into micelles. This shows that the implementation of an acid-base functionality such as an imidazole group in the hydrophobic core of the amphiphilic calix[6]arene makes the aggregation architecture responsive to the pH and to metal ions.


Hip joint contact loads in older adults during recovery from forward loss of balance by stepping.
Hip joint contact loads during activities of daily living are not generally considered high enough to cause acute bone or joint injury. However there is some evidence that hip joint loads may be higher in stumble recovery from loss of balance. A common laboratory method used to evaluate balance recovery performance involves suddenly releasing participants from various static forward lean magnitudes (perturbation intensities). Prior studies have shown that when released from the same perturbation intensity, some older adults are able to recover with a single step, whereas others require multiple steps. The main purpose of this study was to use a musculoskeletal model to determine the effect of three balance perturbation intensities and the use of single versus multiple recovery steps on hip joint contact loads during recovery from forward loss of balance in community dwelling older adults (n=76). We also evaluated the association of peak hip contact loads with perturbation intensity, step length and trunk flexion angle at foot contact at each participant׳s maximum recoverable lean angle (MRLA). Peak hip joint contact loads were computed using muscle force estimates obtained using Static Optimisation and increased as lean magnitude was increased and were on average 32% higher for Single Steppers compared to Multiple Steppers. At the MRLA, peak hip contact loads ranged from 4.3 to 12.7 body weights and multiple linear stepwise regression further revealed that initial lean angle, step length and trunk angle at foot contact together explained 27% of the total variance in hip joint contact load. Overall findings indicated that older adults experience peak hip joint contact loads during maximal balance recovery by stepping that in some cases exceeded loads reported to cause mechanical failure of cadaver femurs. While step length and trunk flexion angle are strong predictors of step recovery performance they are at best moderate predictors of peak hip joint loading.